The enzyme glucokinase (GK), which is mainly found in pancreatic β-cells and liver parenchymal cells, catalyzes the conversion of glucose to glucose-6-phosphate, which is the first step in the metabolism of glucose. Glucokinase is also a rate-controlling enzyme for glucose metabolism in pancreatic β-cells and liver parenchymal cells, which play an important role in whole-body glucose homeostasis.
Liag, Y. et al. (Biochem. J., 309:167-173 (1995)) report the finding that Type II (maturity-onset) diabetes of the young (MODY-2) is caused by loss of function mutations in the glucokinase gene, which suggests that glucokinase also functions as a glucose sensor in humans. Thus, compounds that activate glucokinase and thus increase the sensitivity of the glucokinase sensor system and thereby cause increase in insulin secretion will be useful in the treatment of hyperglycemia and Type II diabetes.
Glucokinase activators have been demonstrated to be effective in enhancing: 1) the effect of glucose on insulin release from isolated rat and human pancreatic islets, and 2) the glucose induction of pancreatic islet glucokinase in isolated cultured rat islets (e.g., Matschinsky, F. M. et al., Diabetes, 55:1 (2006), and (Matschinsky, F. M. et al., eds., Glucokinase and Glycemic Disease, from Basics to Novel Therapeutics, Karger, publ., Ch. 6, pp. 360-378 (2004)). In diabetic animal model studies, glucokinase activators have been demonstrated to stimulate insulin release, enhance glycogen synthesis and reduce hepatic glucose production in pancreatic clamp studies. Importantly, glucokinase activators have been demonstrated to dose-dependently lower blood glucose levels in different standard animal models of type 2 diabetes, such as the ob/ob mouse, db/db mouse and Zucker fa/fa rat in acute single-dose studies and also effectively improved the glucose excursion in both normal C57/BL6J and ob/ob mice in oral glucose tolerance tests (e.g., in Matschinsky, F. M. et al., eds., Glucokinase and Glycemic Disease, from Basics to Novel Therapeutics, Karger, publ., Ch. 6, pp. 360-378 (2004); as well as Fyfe, M. C. et al., Diabetologia, 50:1277 (2007)).
Glucokinase activators have also demonstrated antidiabetic efficacy in chronic animal models of type II diabetes. For instance, in a 9-day study in ob/ob mice, a glucokinase activator improved the overall glucose profile while showing comparable antihyperglycemic effects in oral glucose tolerance tests at the beginning and end of the study (Fyfe, M. C. et al., Diabetologia, 50:1277 (2007)). In another instance, in a chronic 40-week study, a glucokinase activator prevented the development of hyperglycemia in diet-induced obese mice which were glucose intolerant. The diet-induced obese mice treated with a glucokinase activator showed marked improvement in the glucose excursion in an oral glucose tolerance test at the end of the study relative to the control group Matschinsky, F. M. et al., eds., Glucokinase and Glycemic Disease, from Basics to Novel Therapeutics, Karger, publ., Ch. 6, pp. 360-378 (2004)).
Accordingly, compounds that activate glucokinase could demonstrate a wide range of utilities in treating inflammatory, allergic, autoimmune, metabolic, cancer and/or cardiovascular diseases. PCT Publication Nos. WO 2007/007041 A1, WO 2008/005914 A1, WO 2008/154563 A1, WO 2008/005964 A1 (incorporated herein by reference and assigned to present applicant) and WO 2009/018065 A1, disclose compounds that activate glucokinase. The references also disclose various processes to prepare these compounds.
It has also been reported that activation of GK both in the liver and the pancreas could have a profound effect on circulating glucose levels in the diabetic state. However, there are serious concerns that targeting the pancreas could result in the worsening of the diabetic state. In view of this it is desirable to find new compounds that minimize the effects on the pancreas by primarily targeting the liver. (Bebernitz et al., J. Med. Chem. 2009, 52, 6142-6152 and Massa et al., Life, 63(1): 1-6, Jan. 2011).
It is also desirable to find compounds with advantageous and improved characteristics in one or more of the following categories:
(a) pharmaceutical properties (i.e., solubility, permeability, amenability to sustained release formulations);
(b) dosage requirements (e.g., lower dosages and/or once-daily dosing);
(c) factors which decrease blood concentration peak-to-trough characteristics (i.e., clearance and/or volume of distribution);
(d) factors that increase the concentration of active drug at the receptor (i.e., protein binding, volume of distribution, metabolic stability);
(e) factors that decrease the liability for clinical drug-drug interactions (cytochrome P450 enzyme inhibition or induction, such as CYP 2D6 inhibition, see Dresser, G. K. et al., Clin. Pharmacokinet. 38:41-57 (2000), which is hereby incorporated by reference); and
(f) factors that decrease the potential for adverse side-effects (e.g., pharmacological selectivity beyond kinase receptors, potential chemical or metabolic reactivity, limited CNS penetration, ion-channel selectivity). It is especially desirable to find compounds having a desirable combination of the aforementioned pharmacological characteristics.